The rise in mitotic polyploid cells in near-senescence (phase III) of human fibroblast cells has been found to contain diplochromosomes (four chromatids). For tetraploid cells, this translates into 46 pairs of sister chromosomes. It has been suggested, from the increase in numbers of such cells, that they might deviate from expected normal, single chromatid segregations in mitosis. In this study, the polyploid cells with diplochromosomes were shown to segregate by bipolar mitosis into genome-reduced cells. Sister pairs separated from each other and moved as a genomic group of two-chromatid chromosomes to the poles. A tetraploid cell thus became reduced to two diploid cells (i.e., G2-4c in G1), which in the next mitosis could either restore the previous diplochromosomal status and ploidy level or cycle as diploid mitotic cells. The polyploid cells that are programmed for genome reductional division become part of the senescent cell population. In such populations, there is depolyploidization into multinucleated cells (MNCs) that can spawn genome-reduced mitotic offspring cells. These facts are relevant to neoplasticity-associated cytopathologies such as 4n cells as intermediates in Barrett's esophagus, MNCs in human papillomavirus infections, and radiation-associated cell changes. On a cell population level, the bipolar genome reductional division is a source for genetic heterogeneity, generating a continued mixture of polyploid and genome-reduced cells. The only other known case is in the mosquito, but the phenomenon is likely more common than has been thought.